WO2021194927A1 - Composition of antiviral agent for use in prophylactic or post-exposure treatment of infectious or respiratory diseases - Google Patents
Composition of antiviral agent for use in prophylactic or post-exposure treatment of infectious or respiratory diseases Download PDFInfo
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- WO2021194927A1 WO2021194927A1 PCT/US2021/023405 US2021023405W WO2021194927A1 WO 2021194927 A1 WO2021194927 A1 WO 2021194927A1 US 2021023405 W US2021023405 W US 2021023405W WO 2021194927 A1 WO2021194927 A1 WO 2021194927A1
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- QOVAIXZDVMPBDC-HLXLPKMUSA-N C[C@@]1([C@@](c2ccc3[n]2N=C(N)NC3=O)(C#N)O[C@H](CO)[C@H]1O)O Chemical compound C[C@@]1([C@@](c2ccc3[n]2N=C(N)NC3=O)(C#N)O[C@H](CO)[C@H]1O)O QOVAIXZDVMPBDC-HLXLPKMUSA-N 0.000 description 1
- RUSWRQNSXLEGBD-XWWRSZOLSA-N C[C@@]1([C@@](c2cnc3[n]2nc(N)nc3N)(C#N)O[C@H](CO)[C@H]1O)O Chemical compound C[C@@]1([C@@](c2cnc3[n]2nc(N)nc3N)(C#N)O[C@H](CO)[C@H]1O)O RUSWRQNSXLEGBD-XWWRSZOLSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Definitions
- the present invention relates to a drug delivery system for delivery of an antiviral agent.
- the present invention relates to a method of preparing the drug delivery system.
- the present invention also relates to a sustained-release pharmaceutical composition adapted to pulmonary delivery system, which has a reduced systemic side effect.
- Infectious disease could be transmitted by different route of infection such as contact, droplet, and blood-bome infection and bioavailability of drug at affected physical environment could be low by systematic administration of the drug.
- the penetration of drug delivery system onto target cells of the target tissues is the critical obstacle to effectively treating infectious diseases, such as lung infectious diseases via inhalation.
- drug substance retention inside liposome before drug delivery system attachment to the target epithelial cell can alter from one liposomal drug to another liposomal drug based on diffusion rate of free, uncharged drug substance across the lipid membrane of the liposomes, which highly depends on physicochemical properties of the lipid barriers in the presence of microenvironment outside the liposomes, as well as the aqueous environment inside the same.
- Liposome encapsulation of drug substance could alter the pharmacokinetic profile of the drug substance, provide slow drug release at a local physical environment, allow for optimal administered doses with less frequent drug administration, and/or possibly reduces side effects and toxicity.
- quinine compound or other antiviral agents delivered by the liposome as whole would effectively exert required functions, such as deposition onto the target cell lines expressing suitable receptors as docket site for the virus’s entrance to intracellular target sites and perform a desired pharmacokinetic profile in vivo.
- liposome technology to reformulate antiviral agents can yield a liposomal formulation for inhalation at a prophylactic dose to prevent severe acute respiratory syndrome or a therapeutic dose to treat respiratory diseases or infectious diseases with a reduced side effect.
- liposomal drug formulations for inhalation as drug products for chemoprophylaxis as prevention, treatment of mild cases, treatment of acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or severe acute respiratory syndrome (SARS) caused by infection of vims, such as coronavirus, COVID-19, also known as SARS-CoV2.
- the formulation suitable for respiratory diseases should have the following properties: being inhalable, showing enough encapsulation efficiency after nebulization, having an improved stability or proper resistance to destruction by local substances, such as lung surfactant, and furthermore, having desired dose strength to ensure the potential for reaching the desired efficacy in the pulmonary environment.
- the present invention addresses this need and other needs.
- the present invention provides a liposomal drug formulation for treatment of respiratory diseases or infectious diseases, particularly via inhalation, which comprises at least one lipid optionally phospholipid(s) and a sterol, and/or polyethylene glycol (PEG)-modified phospholipid; and an antiviral agent encapsulated in the aqueous interior of the liposome.
- a liposomal drug formulation for treatment of respiratory diseases or infectious diseases particularly via inhalation, which comprises at least one lipid optionally phospholipid(s) and a sterol, and/or polyethylene glycol (PEG)-modified phospholipid; and an antiviral agent encapsulated in the aqueous interior of the liposome.
- composition of antiviral agent comprising liposomal antiviral agent and a predetermined amount of free antiviral agent in an aqueous suspension that can be aerosolized and inhaled for prophylactic or enhanced treatment of respiratory disease.
- liposomal antiviral agent a predetermined amount of free antiviral agent in an aqueous suspension that can be aerosolized and inhaled for prophylactic or enhanced treatment of respiratory disease.
- the present disclosure provides a composition of antiviral agent for use in prophylaxis or treatment of a respiratory disease or an infectious disease, particularly to SARS, having the advantages of: 1) achieving a longer therapeutic effect compared to inhaled free drug substance, 2) delivering the drug directly to the disease site or virus infected site, 3) quicker onset of action, 4) reducing adverse drug reactions and systemic effects, 5) bypassing first-pass metabolism observed in oral dosing, thus increasing the bioavailability of the drug substance (and possibly reducing cardiotoxicity, ocular symptoms of retinopathy, gastrointestinal (GI) effects, including nausea, vomiting, diarrhea and abdominal discomfort and hepatotoxicity), 6) increasing the residence time of the drug substance in target tissue via sustained release from liposomal drug, 7) decreasing the frequency of drug administration, 8) non-invasive inhalation delivery, and/or 9) improving patient outcomes and compliance.
- GI gastrointestinal
- the antiviral agent according to the present disclosure is encapsulated in the liposome at a determined amount to form a composition of antiviral agent according to the present disclosure in order to achieve the composition with a preferred release profile and reduced toxicity, particularly to cardiotoxicity.
- composition of antiviral agent for use in treatment or prophylaxis of respiratory disease which is inhalable and comprises liposomal antiviral agent, wherein the liposomal antiviral agent comprises: a liposome comprising: at least one lipid; and an antiviral agent encapsulated in the liposome.
- the liposome comprises a lipid bilayer composed of one or more phospholipids and a sterol, wherein the sterol is cholesterol, and phospholipid(s): cholesterol is at a molar ratio from 1:1 to 2:1, optionally 3:2.
- the one or more phospholipids includes phosphocholine (PC), which can, but not be limited to hydrogenated soy phosphatidylcholine (HSPC),
- PC phosphocholine
- HSPC hydrogenated soy phosphatidylcholine
- DSPC 1.2-distearoyl-sn-glycero-3-phosphocholine
- the one or more phospholipids comprises DSPC and
- the liposomal antiviral agent comprises 4-aminoquinoline compound.
- the 4-aminoquinoline compound is selected from the group consisting of chloroquine, and hydroxychloroquine and amodiaquine.
- the antiviral agent comprises a nucleoside compound of structural formula I,
- each R 1 , R 2 R 3 , R 4 or R 5 is independently H, OR a , N(R a ) , N 3 , CN, N0 2 , S(0) n R a , halogen or methyl, wherein n is 0, 1 or 2;
- R 7 is H
- Each X 1 or X 2 is independently C-R 10 or N;
- R 8 is halogen, NR n R 12 , N(R n )(OR n ), N R n NR n R 12 , N , NO, NO2, CHO,
- each R 11 or R 12 is independently H, (Ci-Cs)alkyl, (C 2 -Cx)alkenyl, (C 2 -Cx)alkynyl,
- each R b is independently H, alkyl, aryl, arylalkyl or heterocycle; wherein one or more of the non-terminal carbon atoms of each said (Ci-Cs)alkyl is optionally replaced with — O — , — S — or — NR a — .
- the composition of antiviral agent according to the present disclosure further comprises an antibiotic, a supplement, an anti-retroviral agent or combinations thereof.
- antibiotics are penicillins (ampicillin plus sulbactam, piperacillin plus tazobactam, macrolides, cephalosporins, aminoglycosides and glycopep tides.
- the antibiotic is selected from the group consisting of: currimycin and azithromycin.
- the present disclosure also provides a composition of antiviral agent for use in prophylaxis or treatment of an infectious disease or a respiratory disease or an aerosolized composition of particles containing said composition of antiviral agent, which has a drug to lipid ratio of at least 0.01 mol/mol and optionally from 0.01 mol/mol to 2.0 mol/mol, 0.05 mol/mol to 2.0 mol/mol, 0.05 mol/mol to 1.5 mol/mol, 0.05 mol/mol to 1.0 mol/mol, 0.05 mol/mol to 0.5 mol/mol, 0.05 mol/mol to 0.3 mol/mol, 0.05 mol/mol to 0.2 mol/mol, 0.05 mol/mol to 0.15 mol/mol, 0.01 mol/mol to 1 mol/mol, 0.05 mol/mol to 0.1 mol/mol, 0.07 mol/mol to 0.09 mol/mol, or about 0.085 mol/mol; and a concentration of antiviral agent ranging from 0.1 mg
- the present disclosure also provides an aerosolized composition of particles comprising a liposomal quinine compound for use in prophylaxis or treatment of the respiratory disease according to the present disclosure, which has a drug-to-lipid ratio of at least 0.01 mol/mol, optionally at least 0.05 mol/mol, optionally from 0.01 mol/mol to 2.0 mol/mol, 0.05 mol/mol to 2.0 mol/mol, 0.05 mol/mol to 1.5 mol/mol, 0.05 mol/mol to 1.0 mol/mol, 0.05 mol/mol to 0.5 mol/mol, 0.05 mol/mol to 0.3 mol/mol, 0.05 mol/mol to 0.2 mol/mol, 0.05 mol/mol to 0.15 mol/mol, optionally about 0.5 mol/mol; and a concentration of quinine compound ranging from 1 mg/mL to 10 mg/mL on the basis of the composition.
- the present disclosure also provides an aerosolized composition of particles comprising a liposomal nucleoside compound for use in prophylaxis or treatment of the infectious disease according to the present disclosure, which has a drug-to-lipid ratio of at least 0.01 mol/mol, optionally at least 0.05 mol/mol, optionally 0.01 mol/mol to 1 mol/mol, 0.03 mol/mol to 0.5 mol/mol, 0.03 mol/mol to 0.15 mol/mol, 0.03 mol/mol to 0.1 mol/mol, optionally about 0.05 mol/mol, 0.05 mol/mol to 0.5 mol/mol, 0.05 mol/mol to 0.15 mol/mol, 0.05 mol/mol to 0.1 mol/mol, 0.07 mol/mol to 0.1 mol/mol, optionally about 0.085 mol/mol; and a concentration of the nucleoside compound ranging from 0.1 mg/mL to 5 mg/mL on the basis of the composition.
- the present disclosure also provides a nebulized spray comprising the composition of antiviral agent for use according to the present disclosure.
- the present disclosure also provides an aerosolized composition of particles containing the composition of antiviral agent for use in prophylaxis or treatment of a respiratory disease or an infectious disease, which comprises the liposomal antiviral agent according to the present disclosure.
- the present disclosure also provides a method for treating or preventing a respiratory disease or infectious disease, which comprises: administering an effective amount of the composition of antiviral agent for use in treatment or prophylaxis of respiratory disease according to the present disclosure to a subject in need thereof.
- the present disclosure also provides a system for administering a composition of antiviral agent to a subject in need thereof.
- the system comprises the composition of antiviral agent according to the present disclosure and a pulmonary delivery device.
- the pulmonary delivery device is capable of aerosolizing the composition of antiviral agent, whereby after aerosolization formed particles containing the liposomal antiviral agent comprises free antiviral agent in an amount effective to provide immediate antiviral activity and the liposomal antiviral agent in an amount effective to provide sustained antiviral activity.
- the present disclosure also provides a method for reducing complications associated with treatment of a respiratory disease or an infectious disease in a human subject for said complications, which comprises administering the composition according to the present disclosure to a subject in need thereof.
- the complications include, but not limited to cardiotoxicity or hepatotoxicity.
- the complications include, but not limited to prolongation of the corrected QT interval (QTc).
- Figure 1 depicting pharmacokinetic profiles of HCQ in rat lung following administration of the composition according to the present disclosure and free HCQ;
- Figure 2 depicting pharmacokinetic profiles of HCQ in rat blood following administration of the composition according to the present disclosure and free HCQ;
- Figure 3 depicting pharmacokinetic profiles of HCQ in rat heart following administration of the composition according to the present disclosure and free HCQ; and [0030] Figures 4A and 4B showing a series of graphs depicting mean concentration-time profiles of GS-441524 in rat lung (Fig. 4A) and plasma (Fig. 4B) after a single IV administration of SBECD formulated GS-441524 (GS-441524 Solution-IV) or a single IT administration of liposomal GS-441524, also denoted as ISPM21 (ISPM21-IT); LLOQ: lower limit of quantification.
- ISPM21 ISPM21-IT
- LLOQ lower limit of quantification.
- the term “treating” “treated” or “treatment” as used herein includes preventive (e.g. prophylactic), palliative, and curative uses or results.
- the term “subject” includes a vertebrate having respiratory disease or other diseases or suspected to viral infection. Preferably, the subject is a warm-blooded animal, including mammals, preferably humans.
- the term “drug” refers to antiviral agent, such as quinine compound or nucleoside compound which pertains to an activity on desired therapeutic effect in accordance with the present disclosure.
- drug to lipid ratio (D/L)” refers to the ratio of antiviral agent to at least one lipid in the composition according to the present disclosure.
- the drug content in a free form drug or liposomal drug of a composition of liposomal drug according to the present disclosure could, but not be limited to, be determined by UV-Vis absorbance measurements or high-pressure liquid chromatography (HPLC) method.
- the phospholipid content, or concentration, of liposome and liposomal drug could, but not be limited to, be determined by assaying the phosphorus content of liposome and liposomal drug samples using a phosphorus assay (adapted from G. Rouser et al., Lipids 1970, 5, 494-496) or HPLC method.
- pharmacokinetic data were obtained in rats
- correlated pharmacokinetic profiles with the inhaled composition according to the present disclosure could be obtained in other mammals, including, but not limited to, cats, dogs, horses, mice, pigs, non-human primates and humans to develop the inhaled composition.
- infectious disease and pathogenic infection refers to disorders caused by organism, such as viruses, parasites and bacteria.
- the infectious disease was transmitted via fecal-oral transmission, droplet contact, sexual transmission, oral transmission, direct contact, vehicle transmission, vertical transmission, iatrogenic transmission, or vector-borne transmission.
- the infectious disease could include, but not limited to, urinary tract infection, skin infection, respiratory infection, odontogenic infection, vaginal infection and intro- amniotic infection.
- the infectious diseases include, but not limited to: acute flaccid myelitis (AFM), anaplasmosis, anthrax, babesiosis, botulism, brucellosis, campylobacteriosis, carbapenem-resistant infection (CRE/CRPA), chancroid, chikungunya virus infection (chikungunya), chlamydia, ciguatera (harmful algae blooms (HABS)), Clostridium difficile infection, Clostridium perfringens (epsilon toxin), coccidioidomycosis fungal infection (valley fever), covid-19 (coronavirus disease 2019), creutzfeldt-jacob disease, transmissible spongiform encephalopathy (CJD), cryptosporidiosis (crypto), cyclosporiasis, dengue, 1,2, 3, 4 (dengue fever), diphtheria, E.
- AFM acute flaccid myelitis
- coli infection Shiga toxin-producing (STEC), eastern equine encephalitis (EEE), Ebola hemorrhagic fever (Ebola), ehrlichiosis, encephalitis, arbo viral or parainfectious, enterovirus infection , non-polio (non-polio enterovirus), enterovirus infection D68 (EV-D68), giardiasis (giardia), glanders, gonococcal infection (gonorrhea), granuloma inguinale, haemophilus influenza disease, type b (HIB or h-flu), hantavirus pulmonary syndrome (HPS), hemolytic uremic syndrome (HUS), hepatitis A (Hep A), hepatitis B (Hep B), hepatitis C (Hep C), hepatitis D (Hep D), hepatitis E (Hep E), herpes, herpes Zoster, zoster VZV (shingles),
- Respiratory diseases in accordance with the present disclosure include, but are not limited to: acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or severe acute respiratory syndrome (SARS) with main complications including: fluid leaks into the lungs making breathing difficult or impossible.
- ARDS acute respiratory distress syndrome
- ALI acute lung injury
- SARS severe acute respiratory syndrome
- Symptoms typically include fever, cough, productive cough, nonproductive cough, dyspnea and fatigue or myalgia, tightness in the chest, and gradual onset of shortness of breath.
- Complications include pulmonary hypertension, heart failure, pneumonia, or pulmonary embolism.
- composition of the antiviral agent in accordance with the present disclosure is suitable for use in prophylaxis as prevention, treatment of mild cases, treatment of acute respiratory distress syndrome (ARDS), acute lung injury (ALI) or severe acute respiratory syndrome (SARS) caused by coronavirus or the derivatives thereof.
- ARDS acute respiratory distress syndrome
- ALI acute lung injury
- SARS severe acute respiratory syndrome
- liposome or “liposomal” as used herein are directed to a population of vesicles, each vesicle being characterized by having an aqueous interior space sequestered from an outer medium by a membrane of one or more bilayer membranes.
- Bilayer membranes of liposomes are typically formed by one or more lipids, i.e., amphiphilic molecules of synthetic or natural origin that comprise spatially separated hydrophobic and hydrophilic domains.
- the interior aqueous space of the liposome is substantially free of a neutral lipid, such as triglyceride, non-aqueous phase (oil phase), water-oil emulsions, a second liposome or other mixtures containing non-aqueous phase.
- a neutral lipid such as triglyceride, non-aqueous phase (oil phase), water-oil emulsions, a second liposome or other mixtures containing non-aqueous phase.
- Non-limiting examples of liposomes include small unilamellar vesicles (SUV) and large unilamellar vesicles (LUV), and multi-lamellar vesicles (MLV) with an average diameter ranges from 50 nm to 10000 nm, 50 nm to 500 nm, 50 nm to 450 nm, 50 nm to 400 nm, 50 nm to 350 nm, 50 nm to 300 nm, 50 nm to 250 nm,
- SUV small unilamellar vesicles
- LUV large unilamellar vesicles
- MLV multi-lamellar vesicles
- the MLV can be directly formed by a hydrated lipid film, spray-dried powder or lyophilized cake of selected lipid compositions with trapping agent; the SUV and LUV can be sized from MLV by sonication, homogenization, microfluidization or extrusion.
- liposomes comprise a lipid mixture typically including at least one lipid selected from the group consisting of: dialiphatic chain lipids, such as phospholipids, diglycerides, dialiphatic glycolipids; single lipids such as sphingomyelin and glycosphingolipid; sterols such as cholesterol; and derivates thereof, and combinations thereof.
- dialiphatic chain lipids such as phospholipids, diglycerides, dialiphatic glycolipids
- single lipids such as sphingomyelin and glycosphingolipid
- sterols such as cholesterol
- Examples of phospholipids according to the present disclosure include, but are not limited to, 1 ,2-dilauroyl-.v/7-glycero-3-phosphocholine (DLPC),
- DMPC 1.2-dimyristoyl-.s77-glycero-3-phosphocholine
- DPPC 1.2-dipalmitoyl-.s77-glycero-3-phosphocholine
- PSPC pilocatechin-aroyl-.s77-glycero-3-phosphocholine
- POPC pilocatechin-aroyl-.s77-glycero-3-phosphatidylcholine
- DOPC hydrogenated soy phosphatidylcholine
- HSPC hydrogenated soy phosphatidylcholine
- DMPG sodium salt
- DOPG 1.2-dioleoyl-.s77-glycero-3-phospho-( 1 -rac-glycerol)
- DMPS 1.2-dimyrisU yl-.s77-glycero-3-phospho-L-serine (sodium salt) (DMPS),
- DOPS 1.2-dioleoyl-.s77-glycero-3-phospho-L-serine
- DOPS 1,2-dimyristoyl-.v/7-glycero-3-phosphate (sodium salt)
- DPPA 1,2-dipalmitoyl-.v/7-glycero-3-phosphate
- DSPA 1.2-distearoyl-5n-glycero-3 -phosphate (sodium salt)
- DOPA 1.2-dioleoyl-.s77-glycero-3-phosphale (sodium salt)
- DOPE 1.2-dioleoyl-sn-glycero-3-phosphoethanolamine
- DOPI ammonium salt
- EPC L-a-phosphatidylcholine
- EPE L-a-phosphatidylethanolamine
- the liposomal antiviral agent according to the present disclosure optionally incorporates a significant amount of polyethylene glycol (PEG) moiety onto the surface of the vesicles by incorporating a PEG-modified phosphatidylethanolamine (PE) into the membrane of the vesicles to achieve longer, sustained drug release that will be safe, efficacious, and less frequent dosing.
- PEG polyethylene glycol
- PE PEG-modified phosphatidylethanolamine
- the liposomal antiviral agent according to the present disclosure optionally incorporates a significant amount of negative charge moiety onto the surface of the vesicles by incorporating a PEG-modified phosphatidylethanolamine (PE) or fatty acids into the membrane of the vesicles to prevent liposome aggregation or flocculation processes in solution during storage.
- PE PEG-modified phosphatidylethanolamine
- the polyethylene glycol-modified lipid comprises a polyethylene glycol moiety conjugated with a lipid.
- the PEG moiety has a molecular weight from about 5,00 to about 20,000 daltons.
- the PEG-modified lipid is mixed with the phospholipids to form liposomes with one or more bilayer membranes.
- the amount of PEG-modified lipid ranges from 0.0001 mol% to 40 mol%, optionally from 0.001 mol% to 30 mol%, optionally from 0.01 mol% to 20 mol%, optionally from 0.0001 mol% to 10 mol%, optionally from 0.001 mol/% to 5 mol%, and particularly no more than 6 mol%, optionally 5 mol%, 3 mol% or 2 mol%, on the basis of the total phospholipids and sterol.
- the PEG-modified lipid has a PEG moiety with an average molecular weight ranging from 1,000 g/mol to 5,000 g/mol.
- the PEG-modified lipid is phosphatidylethanolamine linked to a polyethylene glycol group (PE-PEG).
- PEG-modified phosphatidylethanolamine is l,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)] (DSPE-PEG).
- the PEG-modified phosphatidylethanolamine (PE) is DSPE-PEG at an amount ranging from 0.0001 mol% to 40 mol%, optionally from 0.01 mol% to 20 mol%, of the total lipid content of the liposomes and has a PEG moiety with an average molecular weight of 2,000 g/mol.
- the terms “liposomal antiviral agent” and “liposomal drug” are interchangeably used in the present disclosure.
- the liposomal antiviral agent in accordance to the present disclosure comprises liposomes with entrapped antiviral agent, which are prepared by encapsulating the antiviral agent in the aqueous interior of the liposome via a transmembrane pH gradient-driven remote loading method.
- the liposomes are formed together with a drug substance, such as hydroxychloroquine or GS-441524, to encapsulate the drug substance in the aqueous interior of the liposome or alone as empty liposomes having a transmembrane gradient for later use in a drug loading process as active loading method, also known as remote loading, to form the liposomal drug.
- a drug substance such as hydroxychloroquine or GS-441524
- the transmembrane pH gradient is created by using a trapping agent for remote loading of the antiviral agent into liposome and the trapping agent is composed of an ammonium compound and an anionic counterion.
- ammonium compound includes non-substituted or substituted ammonium being a cationic ion presented by NR4 + , wherein each R is independently H or an organic residue, and the organic residue is independently alkyl, alkylidene, heterocyclic alkyl, cycloalkyl, aryl, alkenyl, cycloalkenyl, or a hydroxyl-substituted derivative thereof, optionally including within its hydrocarbon chain a S, O, or N atom, forming an ether, ester, thioether, amine, or amide bond.
- the ammonium compound is ammonium.
- anionic counterion refers to an anionic ion or an entity which is covalently linked to one anionic functional group.
- the anionic ion or the anionic functional group has negative electric charge under physiological environment.
- the anionic ion or the anionic functional group can be selected from one or more of the following: sulfate, citrate, sulfonate, phosphate, pyrophosphate, tartrate, succinate, maleate, borate, carboxylate, bicarbonate, glucuronate, chloride, hydroxide, nitrate, cyanate or bromide.
- the anionic ion and the anionic functional group is selected from one or more of the following: citrate, sulfate, sulfonate, phosphate, pyrophosphate and carboxylate.
- the entity linked to the anionic functional group can be a natural or synthetic, organic or inorganic compound.
- the entity include, but are not limited to, a non-polymer substance selected from alkyl group or aryl group, such as benzene, nucleotide and saccharide.
- alkyl refers to a saturated hydrocarbon radical having indicated number of carbon atoms.
- the alkyl is selected from the group consisting of alkyl of 1 to 4 carbons (Ci-4 alkyl), alkyl of 1 to 6 carbons (Ci- 6 alkyl), alkyl of 1 to 8 carbons (Ci- 8 alkyl), alkyl of 1 to 10 carbons (Ci-io alkyl), alkyl of 1 to 12 carbons (Ci-12 alkyl), alkyl of 1 to 14 carbons (Ci-14 alkyl), alkyl of 1 to 16 carbons (C1-16 alkyl), alkyl of 1 to 18 carbons (C1-18 alkyl) and alkyl of 1 to 20 carbons (Ci-20 alkyl).
- the anionic counterion is selected from the group consisting of sulfate, phosphate, citrate, gluconate, sucrose octasulfate, dextran sulfate and combinations thereof.
- the trapping agent is selected from the group consisting of ammonium sulfate, ammonium phosphate, ammonium citrate, ammonium sucrose octasulfate, ammonium dextran sulfate, dimethylammonium sulfate, dimethylammonium phosphate, dimethylammonium citrate, diethylammonium sulfate, diethylammonium phosphate, diethylammonium citrate, diethylammonium sucrose octasulfate, diethylammonium dextran sulfate, trimethylammonium sulfate, trimethylammonium phosphate, trimethylammonium citrate, triethylammonium sulfate, triethylammonium phosphate, triethylammonium citrate, triethylammonium sucrose octasulfate, triethylammonium sucrose
- the liposomal antiviral agent has a mean particle diameter between 50 nm and 1,000 nm.
- Non-limiting examples of the liposomal antiviral agent has an average diameter ranges from 50 nm to 20 pm, 50 nm to 10 pm, 50 nm to 1000 nm, 50 nm to 500 nm, 50 nm to 400 nm, 50 nm to 300 nm, 50 nm to 250 nm, 50 nm to 200 nm, 100 nm to 300 nm or 150 nm to 250 nm.
- the antiviral agent includes, but not be limited to, antimalarial agent, antiretroviral agent or combination thereof.
- the antiviral agent is selected from the group consisting of quinine compound, nucleoside compound and combination thereof.
- quinine compound refers to a substance derived from a lead compound with anti-malarial activity, quinine, extracted from the bark of the cinchona tree.
- Quinine compounds such as hydroxychloroquine, have been shown to be potential in inhibiting exacerbation of pneumonia, improving imaging findings, promoting virus negative conversion, and shortening the disease course.
- systemic administration of quinine compound could show side effects such as blurred vision, nausea, vomiting, abdominal cramps, headache, and diarrhea.
- the quinine compound according to the present disclosure includes but not be limited to quinine and other 4-aminoquinolines, such as quinine, quinidine, cinchonine, cinchonidine, chloroquine (CQ), hydroxychloroquine (HCQ) and the like.
- Exemplary quinine compounds, CQ and HCQ are suggested to be able to prevent the acidification of intracellular organelles and inhibit lysosomal release of viral genome.
- these drugs can interfere with the glycosylation of the angiotensin-converting enzyme-2 (ACE2) receptor on the host cell and reduce binding efficiency between the receptor and spike protein on the surface of the coronavirus.
- ACE2 angiotensin-converting enzyme-2
- nucleosides as inhibitors of nonstructural viral protein, such as RNA-dependent RNA polymerase, being used as potential therapies for RNA vims infections have been reported.
- the nucleosides are expected to be taken up by the cell and converted in vivo to a triphosphate to compete for the polymerase nucleotide binding site to terminate a polymerase chain reaction. This conversion to the triphosphate is commonly mediated by cellular kinases which imparts additional stmctural requirements on a potential nucleoside polymerase inhibitor. Formation of the monophosphate by a nucleoside kinase is generally considered as the rate limiting step of the three phosphorylation events.
- US7,964,580 discloses pronucleosides containing phosphoramidate moiety which are masked with neutral lipophilic groups to obtain a suitable partition coefficient to optimize uptake and transport into the cell dramatically enhancing the intracellular concentration of the nucleoside monophosphate relative to administering the parent nucleoside alone. While there are controversial observations foreseeing the enzyme-mediated hydrolysis of the phosphate ester moiety probably produces a nucleoside itself instead of a target nucleoside monophosphate immediately after circulation before its targeting to the desired site. For instances, via intravenous administration,
- (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,l-f][l,2,4]triazin-7-yl)-3,4-dihydroxy-5-(hydroxymethyl )oxolane-2-carbonitrile also known as GS-441524
- known nucleoside compound is a more stable metabolite of remdesivir than its monophosphate form (Humeniuk R, Mathias A, Cao H, et al. Safety, Tolerability, and Pharmacokinetics of Remdesivir, An Antiviral for Treatment of COVID-19, in Healthy Subjects. Clin Transl Sci. 2020; 13(5): 896-906. doi:10.1111/cts.12840).
- nucleoside compound to a target cellular site enriched with the critical rate limiting nucleoside kinase could be a universal platform solution for avoiding complicated manufacture process of different pronucleosides of a large spectrum of nucleoside compounds.
- the composition of antiviral agent according to the present disclosure further comprises an antibiotic, a supplement, or combinations thereof.
- the antiviral agent comprises one or more 1 ’-substituted carba-nucleoside compounds or 2’ -substituted carba-nucleoside compounds as described in the United States Patent Nos. US8,008,264 and US9, 481704.
- the antiviral agent is directed to nucleoside compounds include but not be limited to 1 ’-substituted carba-nucleoside compound and pharmaceutically acceptable salt thereof.
- the antiviral agent comprises an inhibitor of RNA-dependent RNA viral polymerase, wherein the inhibitor includes nucleoside compound of structural formula (I), each R 1 , R 2 R 3 , R 4 or R 5 is independently H, OR a , N(R a ) 2 , N , CN, N0 2 , S(0) n R a , halogen or methyl, wherein n is 0, 1 or 2;
- R 7 is H
- Each X 1 or X 2 is independently C-R 10 or N;
- R 8 is halogen, NR n R 12 , N(R n )(OR n ), N R n NR n R 12 , N , NO, N0 2 , CHO,
- each R 11 or R 12 is independently H, (Ci-Cs)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl,
- the liposomal antiviral agent comprises: a lipid bilayer comprising: one or more phospholipids, a sterol, and an optional polyethylene glycol (PEG)-modified lipid, particularly to PEG-modified phosphatidylethanolamine (PEG-PE); and an aqueous interior encompassed by the lipid bilayer and containing one or more antiviral agents.
- a lipid bilayer comprising: one or more phospholipids, a sterol, and an optional polyethylene glycol (PEG)-modified lipid, particularly to PEG-modified phosphatidylethanolamine (PEG-PE); and an aqueous interior encompassed by the lipid bilayer and containing one or more antiviral agents.
- PEG polyethylene glycol
- the one or more phospholipids is neutral phospholipid
- the PEG-modified lipid is DSPE-PEG.
- the amount of DSPE-PEG ranges from 0.001 to 5 mol%, optionally from 0.0001 mol% to 40 mol%, optionally less than 6 mol%, optionally ranges from 0.001 mol% to 30 mol% on the basis of the total phospholipids and sterol.
- the composition of liposomal antiviral agent has a drug to lipid ratio (ratio of the antiviral agent to at least one lipid) being at least 0.01 mol/mol to 0.1 mol/mol and comprises: a lipid bilayer comprising: DPPC, cholesterol; and an aqueous interior encompassed by the lipid bilayer and containing the antiviral agent entrapped by a trapping agent, wherein the antiviral agent is
- composition of antiviral agent in accordance with the present disclosure is adapted to preparation of an inhalable aerosolized composition of particles containing the liposomal antiviral agent as previously described.
- the composition can be administered for inhalation either as a nebulized spray or aerosol, or by intrathecal administration ⁇ Inhalation administrations are preferred.
- the overall result is a less frequent administration and an enhanced therapeutic index compared to free drug or parenteral form of the drug.
- the liposomal antiviral agent in the composition is particularly advantageous due to their ability to protect the drug while being compatible with the lung lining or lung surfactant.
- the composition of antiviral agent according to the present disclosure has a drug to lipid ratio (D/L) at least 0.01 mol/mol, optionally at least 0.1 mol/mol, and preferably ranging from 0.05 mol/mol to 1 mol/mol, optionally 0.1 mol/mol to 0.7 mol/mol, optionally 0.15 mol/mol to 0.6 mol/mol and optionally 0.15 mol/mol to 0.2 mol/mol.
- the drug to lipid ratio refers to the molar ratio of the antiviral agent to at least one lipid.
- the at least one lipid comprises a neutral phospholipid and a sterol at a molar ratio of 1:1 or 3:2.
- the neutral phospholipid is DPPC and the sterol is cholesterol.
- the composition of antiviral agent has the at least one lipid at a concentration ranging from 1 mM to 200 mM, from 1 mM to 100 mM, 5 mM to 100 mM, from 10 mM to 180 mM, from 15 mM to 140 mM, from 20 to 160 mM, from 30 mM to 140 mM, and from 40 mM to 120 mM.
- the composition of antiviral agent has the one or more phospholipids at a concentration ranging from 1 mM to 100 mM, 5 mM to 100 mM, from 5 mM to 90 mM, from 10 mM to 80 mM, from 15 mM to 70 mM or from 20 mM to 60 mM.
- the composition of antiviral agent has a total concentration of the quinine compound ranging from 0.1 mg/mL to 80 mg/mL, from 0.5 mg/mL to 60 mg/mL, from 1 to 30 mg/mL and from 2 mg/mL to 15 mg/mL, from 0.5 mg/mL to 70 mg/mL, from 0.5 mg/mL to 60 mg/mL, from 0.5 mg/mL to 50 mg/mL, from 0.5 mg/mL to 40 mg/mL, from 0.5 mg/mL to 30 mg/mL, from 0.5 mg/mL to 20 mg/mL, from 0.5 mg/mL to 10 mg/mL, from 0.5 mg/mL to 8 mg/mL, 0.5 mg/mL to 5 mg/mL, from 1.0 mg/mL to 6 mg/mL, from 1.5 mg/mL to 5.0 mg/mL, from 1.5 mg/mL to 4.0 mg/mL or about 2.0 mg/mL.
- the composition of antiviral agent has the one or more phospholipids at a concentration ranging from 1 mM to 100 mM, 5 mM to 100 mM, from 5 mM to 90 mM, from 10 mM to 80 mM, from 15 mM to 70 mM or from 20 mM to 60 mM; and the drug-to-lipid (D/L) ratio ranges from 0.01 mol/mol to 1 mol/mol, 0.03 mol/mol to 0.5 mol/mol, 0.03 mol/mol to 0.15 mol/mol, 0.03 mol/mol to 0.1 mol/mol, about 0.005 mol/mol, 0.05 mol/mol to 0.1 mol/mol, 0.07 mol/mol to 0.09 mol/mol, or 0.085 mol/mol, wherein the antiviral agent is a 1’- substituted carba- nucleoside compound, 2’- substituted carba- nucleoside compound having a free 5
- the composition of liposomal antiviral agent further has a free form antiviral agent and the free form antiviral agent of the composition according to the present disclosure is at an amount less than 60%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or at a range from 10% to 40%, from 15% to 35%, or from 10% to 30% of the total amount of the antiviral agent of the composition.
- aerosolized composition of particles containing the composition of the present disclosure is generated by aerosolizing the composition with a nebulizer, which is selected from the group consisting of air-jet nebulizer, ultrasonic nebulizer, a vibrating mesh nebulizer, a condensation aerosol generator, an electro-hydrodynamic nebulizer or other pulmonary delivery device known in the art.
- a nebulizer which is selected from the group consisting of air-jet nebulizer, ultrasonic nebulizer, a vibrating mesh nebulizer, a condensation aerosol generator, an electro-hydrodynamic nebulizer or other pulmonary delivery device known in the art.
- the aerosolized composition of particles has a mass median aerodynamic diameter between 0.5 pm and 5 pm, and optionally 1 pm and 3 pm.
- the leakage of the antiviral agent from the liposome of the liposomal antiviral agent in the composition according to the present disclosure leads a portion of the antiviral agent to become in a free form, not entrapped by the liposome.
- the resultant free form antiviral agent in the aerosolized composition is less than 60%, 50%, 40%, 30%, 20%, 10% or 5%; optionally at a controlled percentage ranging from 0.1% to 50%,
- 0.5% to 40% 0.5% to 30%, 0.5% to 20%, 0.5% to 10%, 0.5% to 5%, 10% to 50%, 15% to 45%, 20% to 45%, 25% to 35%.
- the aerosolized composition of particles is subjected to pulmonary delivery to a subject in need to perform a release rate between about 0.5% and 25% of the administered drug dose per hour with complete release of the antiviral agent occurring after a minimum of about 12 to 24 hours.
- Example 1 Stability of the liposomal antiviral agent comprises liposomes with entrapped antiviral agent, which were prepared by active loading or passive loading as known in the art.
- a trapping agent solution e.g. ammonium sulfate (A.S.)
- A.S. ammonium sulfate
- Liposomes could be prepared via the thin- film hydration method or solvent injection method.
- the process for preparing liposomal antiviral agent by solvent injection method is embodied by the method comprising the following steps:
- compositions of antiviral agent according to the present disclosure could be formulated by addition of free form antiviral agent to target at a concentration of the antiviral agent at a concentration of from 1.0 mg/mL to 4 mg/mL, and the antiviral agent to the lipids at ratios of from at least 0.05 mol/mol to 0.30 mol/mol (See below Formulation #4 to #6) on the basis of the whole composition respectively.
- liposomal hydroxychloroquine or chloroquine as prepared in above Sections A and B stored at 4°C could be monitored for at least two weeks or a designed time period.
- Hydroxychloroquine or chloroquine loaded into empty liposomes by active loading with ammonium sulfate or by passive loading to obtain the liposomal drug samples could be studied.
- the drug potency, physicochemical properties of liposomes could be studied over time.
- HCQ liposomal hydroxychloroquine
- TLC19 liposomal hydroxychloroquine
- PK pharmacokinetics
- tissue distribution study in Sprague-Dawley (SD) rats following single-dose intravenous (IV)/ intratracheal (IT) administration of HCQ sulfate solution (Free HCQ) or IT administration of a pilot formulation of TLC19 (Study No. PK20021) was conducted. The study was designed to investigate the tissue distribution, mainly lung, and systemic exposure of HCQ.
- Table 1 A Summary of Study Design (Study No. PK20021)
- HCQ concentration versus time profiles in lung, blood and heart following administration of TLC19 pilot formulation and Free HCQ are illustrated in Fig. 1, Fig. 2 and Fig. 3, respectively.
- Mean PK parameters of HCQ in lung, blood and heart are listed in Table 2.
- Table 2 Mean Pharmacokinetic Parameters of HCQ in Lung, Blood and Heart Following Administration of TLC19 and Free HCQ in Rat (Study No. PK20021) a : T max presented as median. b: unit for lung and heart: mg/g; unit for blood: mg/mL c: unit for lung and heart: hr*pg/g; unit for blood: hr*pg/mL d: not applicable
- the HCQ concentration declined constantly and rapidly, especially in the Free HCQ IT administration group, during the first 24 hours post-dose; the mean HCQ concentration declined from 47.8 pg/g to 2.16 pg/g in IT group and from 9.4 pg/g to 3.77 pg/g in IV group.
- the extent of HCQ deposition in lung was elevated significantly for the TLC19 (pilot formulation) group compared to the Free HCQ group, which is attributed to the sustained-release characteristic of liposomal drug; the TLC19 group sustained release of HCQ in the lung for a certain period of time as the mean HCQ concentration declined from 129 pg/g to 57.1 pg/g during the first 24 hours post-dose after administration of half the Free HCQ dose.
- HCQ was absorbed and distributed to the system rapidly after HCQ administration.
- the median T max of HCQ in blood in three groups was at 0.25 hours after dosing.
- the overall systemic exposures, including C max and AUC, were similar in Free HCQ IV and IT groups.
- C max of HCQ in blood was significantly lower than that of Free HCQ.
- a small amount of HCQ resulted in an initial peak concentration within 1 hour after administration of TLC19 (pilot formulation).
- the remaining HCQ stayed in the lung, allowing for prolonged residence time and constantly low mean blood concentrations of TLC19 (pilot formulation) between 24 to 72 hours post-dose.
- the lower blood HCQ concentration levels observed over time suggest that the HCQ was gradually released at the local site.
- TLC19 (pilot formulation) demonstrated a longer release profile than the unformulated HCQ solution.
- HCQ has been shown to cause cardiac disorder, including prolongation of the corrected QT interval (QTc).
- QTc corrected QT interval
- HCQ PK profile in heart tissue was determined (Fig. 3). TLC19 possessed lower heart exposure (C max ) when compared to HCQ solution. Similar AUCs were observed in all groups when dose is normalized. Considering the lower dose required for local (i.e. IT administration) rather than systemic administration (i.e. oral or IV), these results suggest that TLC19 could cause less cardiotoxicity than conventional HCQ administration.
- Sulfobutylether- -cyclodextrin (SBECD) was purchased from Zibo Qianhui
- SBECD formulated GS-441524 (containing 1.0 mg/mL GS-441524) was prepared by dissolving GS-441524 (antiviral agent) in a 150 mg/mL SBECD solution with a pH of ⁇ 4.4 and was used as test article (1) GS-441524 Solution-IV.
- the study drug liposomal GS-441524, also denoted as ISPM21 was prepared by Taiwan Liposome Company, Ltd., Taiwan. It is composed of GS-441524 encapsulated in liposomes with mean particle size around 200 nm.
- GS-441524 was provided by Formosa Pharmaceuticals, Inc. as a pure, pale yellow powder.
- the liposomes are composed of dipalmitoylphosphatidylcholine (Nippon Fine Chemical co., ltd., Japan) and cholesterol (Dishman, The Netherlands), both of which are natural components of lung surfactant 23 .
- Empty, preformed liposome was prepared via solvent injection. Briefly, appropriate amounts of lipid mixture (l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol) were dissolved in ethanol (J.T. Baker, USA) and injected into an ammonium sulfate solution while stirring at 50°C.
- the size of the liposomes was adjusted to around 200 nm by extrusion through a 0.2 pm polycarbonate membrane at 50°C. Unencapsulated ammonium sulfate and ethanol were removed by diafiltration to obtain the final empty liposome.
- Encapsulation of GS-441524 in liposome was performed using an active loading method. Empty, preformed liposome was mixed with GS-441524 drug solution and incubated at 50°C to obtain the final ISPM21 sample (a liposomal drug suspension), which had a pH between 6 and 7, and was used as test article (2) ISPM21-IT.
- Liposomes could be prepared via the thin-film hydration method or solvent injection method.
- a trapping agent solution e.g. ammonium sulfate (A.S.)
- A.S. ammonium sulfate
- EE encapsulation efficiency
- liposomal nucleoside compound stored at 4°C could be monitored for at least two months or a designed time period.
- Nucleoside compound loaded into empty liposomes with 300 mM of ammonium sulfate or 75 mM of triethylammonium sucrose octasulfate as trapping agent to obtain the liposomal drug samples (Table A) could be studied.
- the drug potency, physicochemical properties of liposomes could be studied over time.
- test article diluting the test article 10-fold by mixing 0.5 mL of each sample of the liposomal antiviral agent with 4.5 mL of SLF (pre-warmed at 37°C) and placing the diluted sample in a 15-mL centrifuge tube;
- the analytical method for determining the nucleoside compound encapsulation efficiency is as follows: a. packing and washing 2 mL of a G50 column with condition solution; b. adding 0.1 mL of the sample to the column, then adding 0.45 mL of an eluent and waiting for the solution to be eluted out; c. adding 0.8 mL of eluent to the column and collecting the eluate as liposomal form; d. disrupting the pre- and post-column samples (the liposome form and the total form) by suitable solvent; and e. measuring the absorbance of the samples at the indicated wavelength using a UV-Vis or HPLC method to determine the drug concentrations of each sample.
- the encapsulation efficiency (EE) of the antiviral agent in the liposomes could be calculated and obtained by the formula: the liposomal form (LF) of the drug divided by the total form (TF) of the drug:
- the releasing profile could be plotted to depict the releasing rate (%) versus time.
- the releasing rate could be calculated by the formula: the initial liposomal form minus liposomal form at each time point and then divide by the initial liposomal form:
- a prolonged release profile of drug substance is desired for improved efficacy and treatment of with lower dosing frequency. Therefore, the selected liposomal antiviral agent with slower or suitable releasing profiles among all formulations and used them in the following toxicity study.
- a total of 48 female SD rats (BioLASCO Taiwan Co., Ltd.) were assigned to one of two treatment groups: (1) GS-441524 Solution-IV: 24 rats received a single dose of 0.20 mg GS-441524 per animal via IV injection; (2) ISPM21-IT: 24 rats received a single dose of 0.20 mg ISPM21 (liposome suspension containing 1.0 mg/mL GS-441524) per animal via IT instillation, which is an administration route used to mimic inhalation in a clinical setting.
- the sampling time points for blood samples were 0.25, 1, 4, 24, and 72 hours post-dose and for lung samples were 0.25, 4, 24, and 72 hours post-dose. All procedures involving animals were performed in TLC animal facility and in accordance with the ethical guidelines of Institutional Animal Care and Use Committee (IACUC) at TLC, Taiwan (#TLC20IACU C037) .
- Blood was collected from jugular veins at scheduled sampling time points into collection tubes with K2EDTA as the anticoagulant. Each collection tube was gently inverted to ensure that samples were completely mixed with the anticoagulant. The actual sampling time was recorded. Collected blood samples were centrifuged at l,500xg for 10 minutes at 2-8°C to obtain plasma. Supernatant plasma was immediately transferred into a labelled microtube. Plasma was transferred to a freezer set at -80°C, if not processed immediately. Plasma harvesting was completed within two hours following blood collection.
- Concentrations of GS-441524 were calculated using MassLynx software. The linear ranges were 10-10000 ng/mL and 0.5-500 ng/mL for lung and plasma assay, respectively.
- PK parameters of GS-441524 were calculated by non-compartmental method applying sparse sampling computation using Phoenix ® WinNonlin ® (version 8.0 or above).
- ISPM21-IT After a single dose administration, ISPM21-IT showed similar PK profile (Fig. 4B) and AUC (Tables 3 and 4) in plasma compared to GS-441524 Solution-IV.
- the plasma half-life of ISPM21-IT (9.98 hours) was slightly longer than that of GS-441524 Solution-IV (7.43 hours).
- ISPM21-IT showed lower systemic exposure (37% of C m ax) in plasma compared to GS-441524 Solution-IV (Table 4).
Abstract
Description
Claims
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JP2022554352A JP2023518694A (en) | 2020-03-22 | 2021-03-22 | Antiviral composition for use in prophylactic or post-exposure treatment of infectious or respiratory disease |
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CA3171394A CA3171394A1 (en) | 2020-03-22 | 2021-03-22 | Composition of antiviral agent for use in prophylactic or post-exposure treatment of infectious or respiratory diseases |
EP21718405.0A EP4125810A1 (en) | 2020-03-22 | 2021-03-22 | Composition of antiviral agent for use in prophylactic or post-exposure treatment of infectious or respiratory diseases |
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CN202180023098.0A CN115315252A (en) | 2020-03-22 | 2021-03-22 | Antiviral composition for preventing or treating infection or respiratory disease after exposure |
US17/912,933 US20230181615A1 (en) | 2020-03-22 | 2021-03-22 | Composition of antiviral agent for use in prophylactic or post-exposure treatment of infectious or respiratory diseases |
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